The mitomycins are a family of compounds having the following general Formula (I): ##STR1##
Mitomycins A, B and C are related to one another as set forth in Table 1 below, the designations X, Y and Z being those of formula I.
TABLE 1 ______________________________________ Mitomycin: X Y Z ______________________________________ A --OCH.sub.3 --OCH.sub.3 --H B --OCH.sub.3 --OH --CH.sub.3 C --NH.sub.2 --OCH.sub.3 --H ______________________________________
Mitomycins are derived from mitosane compounds having the following skeleton (II): ##STR2##
The mitosanes are formed during the cultivation of the microorganism Streptomyces caespitosus in a liquid nutrient medium under artificially controlled conditions. After separating the resulting mycellium, the various mitomycins may be isolated from the latter by active carbon or preferably non-ion exchange resin adsorption, organic solvent extraction or chromatography on alumina, as disclosed in U.S. Pat. No. 3,660,578 to Hata et al.
Although the mitosanes are excellent antibiotics, they have limited utility due to their toxicity to human blood (see U.S. Pat. No. 3,450,705 to Matsui et al.). The relatively highly toxic nature of the compounds has prompted search for derivatives of mitomycin to increase the antibiotic activity and to decrease toxicity.
For example, Matsui et al., U.S. Pat. No. 3,450,705, disclose mitomycin compounds substituted at the 7-position with amino, lower alkylamino, phenylamino, or pyridyl, and substituted at the 1a position with haloalkanoyl, halobenzoyl, nitrobenzoyl, alkenoyl, acetyl, glycyl, sorboyl, or acetyl methionyl.
Matsui et al., U.S. Pat. No. 3,558,651, disclose mitosane derivatives comprising 1a-acyl-7-acyloxy-9a-methoxy compounds.
Certain mitomycins and mitomycin derivatives also possess antitumor activity. Oboshi et al., Gann 58: 315-321 (1967); Usubuchi et al., Gann 58: 307-313 (1967); Matsui et al., J. Antibiotics XXI: 189-198 (1968); Japanese Patent No. 68 06 627 to Matsui et al. (Chemical Abstracts 69: 86986k (1968)); and Cheng et al., J. Med. Chem. 20: 767-770 (1977).
While mitomycin C is active against a relatively broad spectrum of experimental tumors, its toxicity and myelosuppressive effects limit its use in clinical practice (Mitomycin C: Current Status and New Developments, Carter et al. (eds.), Academic Press, New York (1979)). In preclinical and clinical studies, mitomycin C has shown activity against a variety of murine and human neoplasms, but has also shown severe, delayed bone marrow toxicity. Goldin, A., et al., NCI-EORTC Symposium on Mitomycin C, Brussels, Belgium (1981).
In other studies, a combination of 5-fluorouracil, adriamycin and mitomycin C was found to be effective for the treatment of patients with advanced gastric and colorectal cancer. This regimen incorporated mitomycin C administration in a single dose schedule every two months, to decrease the treatment-limiting delayed myelosuppressive effects of the compound. Schein, P.S., et al., Mitomycin C: Current Status and New Developments, pp. 133-143, Carter et al. (eds.), Academic Press, New York (1979).
Numerous synthetic derivatives of mitomycin C have been prepared in the hope of obtaining compounds with improved therapeutic properties. These derivatives include substitution on the aziridine ring, carbamoyl, or acyl group substitution on the hydroxymethyl side chain, and replacement of the 7-substituent in the quinone ring with other functional groups, especially substituted amines. However, as disclosed by Remers, U.S. Pat. No. 4,268,676, none of these analogs have emerged as a clinical agent, with the possible exception of the 7-hydroxy analog of the mitomycin C, which has been involved in a recent study in Japan. This analog is asserted to be less leukopenic than mitomycin C, but is also less potent. Also disclosed by Remers, supra, are totally synthetic mitomycin analogs of the mitosane type (Mott et al., J. Med. Chem. 21: 493 (1978)), prepared mainly for their antibacterial activity.
Kinoshita, S., et al., J. Med. Chem. 14: 103-112 (1971), disclose several derivatives of mitomycin substituted in the 1a, 7, and 9a positions. In particular, compounds substituted at the 1a position with sulfonyl, ortho-substituted benzoyl, and acyl derivatives were reported.
Iyengar, B.S., et al., J. Med. Chem. 24: 975-981 (1981), disclose a series of 31 mitomycin C and porfiromycin analogues with various substituents at the 7- and 1a-positions. The most active substituents at the 7-position included aziridine, 2-methylaziridine, proparylamine, furfurylamine, methyl glycinate and 3-aminopyridine.
Iyengar, B., et al., J. Med. Chem. 26: 16-20 (1983), disclose a series of 7-substituted mitomycin C and porfiromycin derivatives and the screening thereof in standard antitumor systems. The authors report that the 7-position controls the reduction of the quinone ring, thus suggesting that it would be possible to alter the substitution of the 7-position to gain selectivity between normal cells and certain cancer cells.
Iyengar, B.S., et al., J. Med. Chem. 26: 1453-1457 (1983), disclose 20 mitomycin C analogues substituted with secondary amines at the 7-position. Eleven of these analogues were more active than mitomycin C against P388 murine leukemia and two of these eleven were significantly less leukopenic. The authors report that no quantitative correlation between antitumor activity and physiochemical properties of the analogues was evident, although the relative ease of quinone reduction may be related to activity.
Iyengar, B.S., et al., J. Med. Chem. 29: 1864-1868 (1986), disclose the preparation of 7-substituted amino 1,2-aziridinomitosenes. The authors reported that a methyl group on the aziridine nitrogen gave increased potency. The 7-amino mitosene derivatives which were difficult to reduce to hydroquinones were essentially inactive.
Sami, S., et al., J. Med. Chem. 27: 701-708 (1984), disclose a series of 30 N.sup.7 -phenyl-substituted mitomycin C analogs. Two of the compounds having pyrazolyl or aminopyridyl substituents at the 7-position were disclosed as clearly superior to mitomycin C in activity against P388 murine leukemia.
Sami, T., et al., J. Med. Chem. 22: 247-250 (1979), also disclose N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of glycosylamines, including three disaccharide derivatives which exhibited strong antitumor activity against leukemia 1210 in mice. In addition, glucopyranose derivatives of N-nitrosoureas possess immunogenic and marrow-sparing properties. Anderson et al., Cancer Research 35: 761-765 (1975); Panasci et al., J. Clin. Invest. 64: 1103-1111 (1979).
In U.S. Pat. No. 4,720,543, compounds having the following general Formula (III) are disclosed: ##STR3## where R.sup.1 is selected from the group consisting of NH.sub.2, C.sub.1 -C.sub.4 alkoxy and a glycosyl residue; and
R.sup.2 is selected from the group consisting of H, C.sub.1 -C.sub.4 alkyl, and a glycosyl residue, with the proviso that either R.sub.1 or R.sub.2, but not both, contain a glycosyl group. PA1 Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, and 2-amino-1,3-cyclohexanediol, or a hydroxyl-protected derivative thereof or the corresponding aminosaccharide, diaminosaccharide or triamino saccharide; PA1 R is hydrogen; PA1 R.sup.1 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C.sub.1 -C.sub.4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazole or carbamyl; or PA1 R and R.sup.1 together form a five or six membered nitrogen containing ring. PA1 R.sup.3 is a 2-(3-cyano-4-morpholinyl)-2-deoxypyranosyl saccharide or a 2-(4-morpholinyl)-2-deoxypyranosyl saccharide. PA1 A is C.sub.1 -C.sub.4 straight or branched alkylene or unsaturated alkylene, phenylene, substituted phenylene, benzylene (--CH.sub.2 Ph--), substituted benzylene, heteroaryl, substituted heteroaryl, or C.sub.3 -C.sub.6 -heterocycloalkyl; PA1 n is 0 or 1; PA1 n.sub.1 is 0 or 1; PA1 A.sub.1 is oxygen, C.sub.1 -C.sub.4 straight or branched saturated or unsaturated alkylene, --C(.dbd.O)--NH--, or --NH--C(.dbd.O)--; PA1 A.sub.2 is oxygen, C.sub.1 -C.sub.4 straight or branched saturated or unsaturated alkylene, NH, NR, or --NH--C(.dbd.O)--; PA1 n.sub.2 is 0 or 1; PA1 Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, and 1,3-cyclohexanediol-2-yl, or a hydroxyl-protected derivative thereof or the corresponding aminosaccharide, diaminosaccharide or triaminosaccharide; or branched saturated or unsaturated alkylene; with the further proviso that when n is 0, then one of n.sub.1 and n.sub.2 is 0. PA1 A is C.sub.1 -C.sub.4 straight or branched alkylene or unsaturated alkylene, phenylene, substituted phenylene, benzylene (--CH.sub.2 Ph--), substituted benzylene, heteroaryl, substituted heteroaryl, or C.sub.3 -C.sub.6 -heterocycloalkyl; PA1 Q.sup.a and Q.sup.b are an alkaline metal, glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, 1,3-cyclohexanediol-2-yl-, or a protected derivative thereof or the corresponding aminosaccharide, diaminosaccharide or triaminosaccharide, or a group of the Formula (IX): ##STR9## wherein R.sup.1 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C.sub.1 -C.sub.4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamoyl; PA1 q=0-4 PA1 A and A.sub.1 are C.sub.1 -C.sub.4 straight or branched alkylene or unsaturated alkylene, phenylene, substituted phenylene, benzylene (--CH.sub.2 Ph--), substituted benzylene, heteroaryl, substituted heteroaryl, or C.sub.3 -C.sub.6 -heterocycloalkyl; PA1 Q.sup.a and Q.sup.b are an alkaline metal, glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, 1,3-cyclohexanediol-2-yl-, or a protected derivative thereof or the corresponding aminosaccharide, diaminosaccharide or triaminosaccharide, or a group of the Formula (IX): ##STR11## wherein R.sup.1 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C.sub.1 -C.sub.4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamoyl; PA1 q=0-4. PA1 Y is selected from the group the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, and 1,3-cyclohexanediol-2-yl, or a hydroxyl-protected derivative thereof or the corresponding aminosaccharide, diaminosaccharide or triaminosaccharide; PA1 R is hydrogen; PA1 R.sup.1 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C.sub.1 -C.sub.4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazole or carbamyl; or PA1 R and R.sup.1 together form a five or six membered nitrogen containing ring; PA1 R.sup.3 is a 2-(3-cyano-4-morpholinyl)-2-deoxy saccharide; PA1 R.sup.3 is a (4-morpholinyl)-2-deoxy saccharide; PA1 Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, and 1,3-cyclohexanediol-2-yl or the corresponding aminosaccharide, diaminosaccharide or triaminosaccharide; PA1 R is hydrogen; PA1 R.sup.1 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C.sub.1 -C.sub.4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazole or carbamyl; or PA1 R and R.sup.1 together form a five or six membered nitrogen containing ring; PA1 R.sup.2 is NH.sub.2 --; PA1 Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, and 1,3-cyclohexanediol-2-yl or the corresponding aminosaccharide, diaminosaccharide or triaminosaccharide; PA1 R is hydrogen; PA1 R.sup.1 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C.sub.1 -C.sub.4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazole or carbamyl; or PA1 R and R.sup.1 together form a five or six membered nitrogen containing ring; PA1 R.sup.2 is CH.sub.3 O--; PA1 A is C.sub.1 -C.sub.4 straight or branched alkylene or unsaturated alkylene, phenylene, substituted phenylene, benzylene (--CH.sub.2 Ph--), substituted benzylene, heteroaryl, substituted heteroaryl, or C.sub.3 -C.sub.6 -heterocycloalkyl; PA1 n is 0; PA1 n.sub.1 is 1; PA1 A.sub.1 is oxygen; PA1 n.sub.2 is 0; PA1 Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, and glucofuranosyl, maltosyl, or a hydroxyl-protected derivative thereof or the corresponding aminosaccharide, diaminosaccharide or triaminosaccharide; PA1 n.sub.2 is 1; PA1 A.sub.2 is --NH--C(.dbd.O)--; and PA1 R, A, and Y are defined above; PA1 n.sub.1 is 0 or 1; PA1 n.sub.2 is 0; PA1 A.sub.1 is a C.sub.1 -C.sub.4 straight or branched saturated or unsaturated alkylene; PA1 A is C.sub.1 -C.sub.4 straight or branched alkylene or unsaturated alkylene, phenylene, substituted phenylene, benzylene (--CH.sub.2 Ph--), substituted benzylene, heteroaryl, substituted heteroaryl, or C.sub.3 -C.sub.6 -heterocycloalkyl; PA1 Q.sup.a and Q.sup.b are an alkaline metal, glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, 1,3-cyclohexanediol-2-yl-, or a protected derivative thereof or the corresponding aminosaccharide, diaminosaccharide or triaminosaccharide, or a group of the Formula (IX): ##STR26## wherein R.sup.1 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C.sub.1 -C.sub.4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamoyl; PA1 q=0-4; PA1 A and A.sub.1 are C.sub.1 -C.sub.4 straight or branched alkylene or unsaturated alkylene, phenylene, substituted phenylene, benzylene (--CH.sub.2 Ph--), substituted benzylene, heteroaryl, substituted heteroaryl, or C.sub.3 -C.sub.6 -heterocycloalkyl; PA1 Q.sup.a and Q.sup.b are an alkaline metal, glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, 1,3-cyclohexanediol-2-yl-, or a protected derivative thereof or the corresponding aminosaccharide, diaminosaccharide or triaminosaccharide, or a group of the Formula (IX): ##STR30## wherein R.sup.1 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C.sub.1 -C.sub.4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamoyl; PA1 q=0-4;
The compounds represented by Formula (III) have excellent anti-neoplastic activity and at the same time possess reduced bone marrow toxicity and lower overall toxicity.
Despite the above-listed mitomycin derivatives, a need continues to exist for improved mitomycin derivatives having good anti-neoplastic properties and low bone marrow and overall toxicity.